CN110668991A - 1, 6-eneyne compound cyanoalkylation reaction method - Google Patents
1, 6-eneyne compound cyanoalkylation reaction method Download PDFInfo
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Abstract
The invention relates to a regioselective cyanoalkylation/cyclization reaction method of 1, 6-eneyne compounds and azo alkyl nitriles under a catalyst-free and additive-free system. The method comprises the steps of adding a 1, 6-eneyne compound, an azoalkyl nitrile compound and a solvent into a Schlenk reaction bottle, and stirring and reacting at a certain temperature under the air atmosphere condition to obtain a product 2-pyrrolidone compound.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a regioselective cyanoalkylation/cyclization reaction method of a 1, 6-eneyne compound and azoalkylnitrile under a catalyst-free and additive-free system.
Background
In polymer chemistry, azoalkylnitriles are widely used as free radical initiators. Traditionally, they only initiate free radical processes and do not participate in chemical reactions. In recent years, azoalkylnitriles have been used as safe and low-toxic cyanating agents in systems in which copper catalysts and/or oxidizing agents are present. In addition, since the azoalkylnitrile is very easily decomposed during heating to generate a cyanoalkyl radical, it is widely used as a cyanoalkylating reagent in organic synthesis. In this context, chemists have developed cyanoalkylation of azoalkylnitriles with alkene and alkyne derivatives. However, the cyanoalkylation reaction of the azoalkylnitrile with the enyne derivative under a catalyst-free and additive-free system has not been reported.
The inventor carries out intensive research on the cyanoalkyl radical reaction under a catalyst-free and additive-free system, and in the invention, the inventor provides a novel method for carrying out high-area selective cyanoalkylation/cyclization reaction on a 1, 6-eneyne compound and an azoalkyl nitrile as reaction raw materials through a radical process under a catalyst-free and additive-free system.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a green, efficient, low-cost and high-selectivity cyanoalkylation/cyclization reaction method of 1, 6-eneyne compounds and azo alkyl nitriles, which does not need any catalyst or additive, and prepares and obtains 2-pyrrolidone compounds at high yield in high regioselectivity at mild temperature.
The cyanoalkylation/cyclization reaction method provided by the invention takes 1, 6-eneyne compounds and azo alkyl nitrile as raw materials, and is prepared by the following steps:
adding a 1, 6-eneyne compound shown in formula 1, an azoalkyl nitrile shown in formula 2 and a solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and carrying out post-treatment to obtain a cyclized product 2-pyrrolidone compound (I).
The chemical reaction formula of the method for high-regioselectivity free radical cyanoalkylation/cyclization reaction of 1, 6-eneyne and azoalkylnitrile provided by the invention can be expressed as (see formula I):
in the reaction of the first formula, the reaction atmosphere may be an air atmosphere of 1atm, and a nitrogen atmosphere of 1atm or other inert gas atmosphere may be used instead.
The post-processing operation is as follows: extracting the reaction solution after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 2-pyrrolidone compound (I).
Formula 1, formula 2 and formula IIn the compound, R1Selected from hydrogen, C5-C14Aryl radical, C1-C10Alkyl radical, C1-C6An acyl group;
R2selected from hydrogen, C1-C6Alkyl radical, C5-C14An aryl group;
R3is selected from C1-C8Alkyl radical, C5-C14An aryl group;
R4is selected from C1-C6Alkyl radical, C5-C14An aryl group;
R5is selected from C1-C6Alkyl radical, C5-C14An aryl group;
wherein each R is1-R5The aryl, alkyl and acyl groups having the number of carbon atoms in the substituents are optionally substituted by a substituent selected from the group consisting of halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5- C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
EWG ═ CN or COOMe.
Preferably, R1Is selected from C1-C10Alkyl radical, C5-C14An aryl group; wherein said C1-C10Alkyl radical, C5- C14Aryl is optionally substituted by a substituent selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
R2selected from hydrogen;
R3is selected from C1-C8Alkyl radical, C5-C14Aryl, wherein said C1-C6Alkyl radical, C5-C14Aryl is optionally substituted by a substituent selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
R4is selected from C1-C6An alkyl group;
R5is selected from C1-C6An alkyl group.
In the reaction of the invention, the solvent is selected from any one or a mixture of more of ethyl acetate, acetonitrile, toluene, N-dimethylformamide and water. Acetonitrile is preferred.
In the reaction of the present invention, the certain temperature is 40 to 80 ℃ and the temperature is most preferably 60 ℃.
In the reaction of the present invention, the time required for complete conversion of the reaction raw materials is 12 to 20 hours, preferably 16 hours.
In the reaction of the present invention, the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 1.2 to 1: 3. Preferably, the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 2.
The invention has the beneficial effects that: a process for the regioselective radical cyanoalkylation/cyclization of 1, 6-enyne compounds with azoalkylnitriles in the absence of catalyst or additive is disclosed, which can obtain a series of target products in high yield without the aid of any catalyst or additive. The method has the advantages of wide reaction substrate application range, simplicity, high efficiency, economy and greenness, and is particularly suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, if not otherwise specified, are commercially available and/or may be prepared according to known methods.
Examples 1-10 were experiments optimized for reaction conditions.
Example 1
Adding a 1, 6-eneyne compound (39.8mg, 0.2mmol) shown in formula 1a, an azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-1 (71% yield);1H NMR (500MHz，CDCl3)δ：7.70(d，J＝8.0Hz，2H)，7.40(t，J＝8.0Hz，2H)，7.19(t，J＝7.5Hz，1H)， 5.43(t，J＝2.0Hz，1H)，5.34(t，J＝2.5Hz，1H)，4.71-4.6g(m，1H)，4.56-4.52(m，1H)，2.1g(d，J ＝14.5Hz，1H)，1.96(d，J＝14.5Hz，1H)，1.41(s，3H)，1.37(s，3H)，1.30(s，3H)；13C NMR(125 MHz，CDCl3)δ：176.0，142.7，138.8，129.1，125.1，124.5，120.2，111.1，52.2，48.5，47.7，30.9，30.5， 29.1，26.9；HRMSm/z(ESI)calcd for C17H21N2O([M+H]+)269.1648，found 269.1649。
example 2
The solvent was changed to ethyl acetate with acetonitrile (2mL), and the same procedure as in example 1 was repeated, whereby the desired product I-1 was obtained in a yield of 80%.
Example 3
The solvent was changed to ethyl acetate with toluene (2mL) and the same procedure as in example 1 was repeated to give the desired product I-1 in a yield of 32%.
Example 4
The solvent was replaced with N, N-dimethylformamide (2mL) and the same procedure as in example 1 was repeated except that the desired product I-1 was obtained in a yield of 51%.
Example 5
The solvent was replaced with water (2mL) and ethyl acetate under the same conditions as in example 1 to give the desired product I-1 in a yield of 5%.
Example 6
Cuprous iodide (CuI, 7.6mg, 0.04mmol) as a catalyst was added under the same conditions as in example 2 to obtain the desired product I-1 in a yield of 81%.
Example 7
The amount of the azoalkylnitrile used was 1.2 equivalents (39.4mg, 0.24mmol), and the other conditions were the same as in example 2, whereby the yield of the objective product I-1 was 53%.
Example 8
The amount of the azoalkylnitrile used was 3 equivalents (98.4mg, 0.6mmol), and the other conditions were the same as in example 2, whereby the yield of the objective product I-1 was 81%.
Example 9
The reaction temperature was reduced to 40 ℃ and the other conditions were the same as in example 2, giving a yield of the target product I-1 of 23%.
Example 10
The reaction temperature was raised to 80 ℃ and the other conditions were the same as in example 2, giving the desired product I-1 in 71% yield.
As can be seen from the above-mentioned examples 1 to 10, the optimum reaction conditions are those of example 2, i.e., the amount of the azoalkylnitrile used is 2 equivalents (65.6mg, 0.4mmol), the solvent is acetonitrile (2mL), and the reaction temperature is 60 ℃. On the basis of obtaining the optimal reaction conditions, the inventor further selects 1, 6-eneyne compounds with different substituents and azoalkylnitriles as raw materials under the optimal reaction conditions to develop a high-region-selectivity free radical cyanoalkylation/cyclization reaction method.
Example 11
A Schlenk flask was charged with a 1, 6-enyne compound represented by formula 1b (45.8mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6mg, 0.4mmol), and ethyl acetate (2mL), and the reactor was then placed under an air atmosphere of 6Stirring and reacting at the temperature of 0 ℃, monitoring the reaction process by TLC until the raw materials disappear (the reaction time is 16 hours), concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is finished, and separating the residue by column chromatography (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-2(84 percent yield);1H NMR (500MHz，CDCl3)δ：7.59(d，J＝9.0Hz，2H)，6.93(d，J＝9.0Hz，2H)，5.41(t，J＝3.0Hz，1H)， 5.32(t，J＝2.0Hz，1H)，4.67-4.63(m，1H)，4.51-4.47(m，1H)，3.81(s，3H)，2.17(d，J＝14.5Hz， 1H)，1.94(d，J＝14.5Hz，1H)，1.40(s，3H)，1.36(s，3H)，1.30(s，3H)；13C NMR(125MHz，CDCl3)δ：175.5，157.0，143.0，132.0，124.6，122.0，114.3，110.9，55.5，52.6，48.2，47.8，30.9，30.5，29.1， 27.0；HRMS m/z(ESI)calcd for C18H23N2O2([M+H]+)299.1754，found 299.1756。
example 12
Adding a 1, 6-eneyne compound (42.6mg, 0.2mmol) shown in formula 1c, an azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, stirring the reactor at 60 ℃ in an air atmosphere for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 16 hours), concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is finished, and separating the residue by column chromatography (the eluting solvent is ethyl acetate/n-hexane) to obtain a target product I-3 (82% yield);1H NMR (500MHz，CDCl3)δ：7.57(d，J＝8.5Hz，2H)，7.20(d，J＝8.0Hz，2H)，5.42(t，J＝2.0Hz，1H)， 5.33(t，J＝2.0Hz，1H)，4.69-4.65(m，1H)，4.52-4.49(m，1H)，2.34(s，3H)，2.16(d，J＝14.5Hz， 1H)，1.94(d，J＝14.5Hz，1H)，1.40(s，3H)，1.36(s，3H)，1.29(s，3H)；13CNMR(125MHz，CDCl3)δ：175.8，142.9，136.3，134.8，129.6，124.6，120.2，110.9，52.3，48.4，47.8，30.9，30.5，29.1，26.9， 20.9；HRMS m/z(ESI)calcd for C18H23N2O([M+H]+)283.1805，found 283.1806。
example 13
Adding a 1, 6-eneyne compound (43.4mg, 0.2mmol) shown in formula 1d, an azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-4 (78% yield);1H NMR (500MHz，CDCl3)δ：7.68-7.65(m，2H)，7.10-7.06(m，2H)，5.43(t，J＝2.0Hz，1H)，5.33(t，J＝ 2.0Hz，1H)，4.68-4.65(m，1H)，4.53-4.50(m，1H)，2.18(d，J＝14.5Hz，1H)，1.94(d，J＝14.5Hz， 1H)，1.41(s，3H)，1.37(s，3H)，1.30(s，3H)；13C NMR(125MHz，CDCl3)δ：175.9，142.7，134.8， 129.3(d，JC-F＝7.5Hz)，124.4，122.1(d，JC-F＝7.5Hz)，115.7(d，JC-F＝22.5Hz)，111.1，52.5，48.3，47.8，30.9，30.4，29.1，27.3；19F NMR(471MHz，CDCl3)δ：-116.9；HRMS m/z(ESI)calcd for C17H20FN2O([M+H]+)287.1554，found287.1555。
example 14
A Schlenk flask was charged with a 1, 6-enyne compound represented by formula 1e (46.6mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6mg, 0.4mmol), and ethyl acetate (2mL), and the reaction vessel was stirred under an air atmosphere at 60 ℃ to monitor the progress of the reaction by TLC until the starting material disappeared (reaction time)16 hours), after completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (elution solvent: ethyl acetate/n-hexane) to obtain a target product I-5 (77% yield);1H NMR (500MHz，CDCl3)δ：7.67(d，J＝9.0Hz，2H)，7.35(d，J＝9.0Hz，2H)，5.43(t，J＝2.5Hz，1H)， 5.34(t，J＝2.0Hz，1H)，4.68-4.64(m，1H)，4.52-4.49(m，1H)，2.17(d，J＝14.5Hz，1H)，1.94(d， J＝14.5Hz，1H)，1.40(s，3H)，1.37(s，3H)，1.29(s，3H)；13CNMR(125MHz，CDCl3)δ：176.1， 142.5，137.3，130.2，129.1，124.4，121.3，111.2，52.2，48.5，47.8，30.8，30.4，29.1，27.3；HRMS m/z (ESI)calcd for C17H20ClN2O([M+H]+)303.1259，found 303.1260。
example 15
Adding a 1, 6-eneyne compound (50.6mg, 0.2mmol) shown in formula 1f, an azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-6 (71% yield);1H NMR (500MHz，CDCl3)δ：7.88(d，J＝8.5Hz，2H)，7.65(d，J＝8.5Hz，2H)，5.46(t，J＝2.0Hz，1H)， 5.36(t，J＝2.0Hz，1H)，4.73-4.70(m，1H)，4.58-4.55(m，1H)，2.20(d，J＝14.5Hz，1H)，1.96(d， J＝14.5Hz，1H)，1.41(s，3H)，1.39(s，3H)，1.30(s，3H)；13CNMR(125MHz，CDCl3)δ：176.6， 142.2，141.7，126.8(q，JC-F＝30.0Hz)，126.2(q，JC-F＝2.7Hz)，124.3，119.6，119.3，111.4，52.0， 48.7，47.8，30.8，30.4，29.1，27.4；19F NMR(471MHz，CDCl3)δ：-62.2；HRMS m/z(ESI)calcd for C18H20F3N2O([M+H]+)337.1522，found337.1524。
example 16
Adding formula 1g of 1, 6-eneyne compound (44.8mg, 0.2mmol) shown in formula 2a, azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, stirring the reactor at 60 ℃ in an air atmosphere for reaction, monitoring the reaction progress by TLC until the raw materials disappear (the reaction time is 16 hours), concentrating the reaction liquid under reduced pressure to remove the solvent after the reaction is finished, and performing column chromatography on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-7 (62% yield);1H NMR (500MHz，CDCl3)δ：7.89(d，J＝8.5Hz，2H)，7.68(d，J＝9.0Hz，2H)，5.47(t，J＝1.5Hz，1H)， 5.36(t，J＝3.0Hz，1H)，4.72-4.68(m，1H)，4.57-4.54(m，1H)，2.20(d，J＝14.5Hz，1H)，1.95(d， J＝14.5Hz，1H)，1.41(s，3H)，1.38(s，3H)，1.29(s，3H)；13CNMR(125MHz，CDCl3)δ：176.9， 142.4，141.9，133.8，133.2，119.7，114.5，111.5，107.8，51.8，48.8，47.9，30.7，30.4，29.1，27.7； HRMS m/z(ESI)calcd for C18H20N3O([M+H]+)294.1601，found 294.1603。
example 17
A Schlenk flask was charged with a 1, 6-enyne compound represented by formula 1i (55.0mg, 0.2mmol), an azoalkylnitrile represented by formula 2a (65.6mg, 0.4mmol), and ethyl acetate (2mL), and the reaction vessel was stirred under an air atmosphere at 60 ℃ to conduct a reaction, progress of the reaction was monitored by TLC until the starting material disappeared (reaction time: 16 hours), after completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography (eluting the solvent)Comprises the following steps: ethyl acetate/n-hexane) to obtain a target product I-8 (75% yield);1H NMR (500MHz，CDCl3)δ：7.34-7.30(m，4H)，7.17-7.13(m，6H)，5.53(t，J＝2.0Hz，1H)，5.44(t，J＝ 2.5Hz，1H)，4.30-4.27(m，1H)，3.50-3.47(m，1H)，3.19(d，J＝12.5Hz，1H)，2.67(d，J＝12.5Hz， 1H)，2.36(d，J＝14.5Hz，1H)，2.13(d，J＝14.5Hz，1H)，1.46(s，3H)，1.36(s，3H)；13C NMR(125 MHz，CDCl3)δ：174.4，140.2，138.3，135.1，130.5，128.9，127.9，127.0，125.4，124.8，121.2，112.2， 54.8，52.9，48.6，46.1，31.4，30.4，27.2；HRMS m/z(ESI)calcd for C23H25N2O([M+H]+)345.1961， found 345.1964。
example 18
Adding a 1, 6-eneyne compound (52.2mg, 0.2mmol) shown in formula 1j, an azoalkylnitrile (65.6mg, 0.4mmol) shown in formula 2a and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-9 (68% yield);1H NMR (500MHz，CDCl3)δ：7.34-7.30(m，4H)，7.17-7.13(m，6H)，5.53(t，J＝2.0Hz，1H)，5.44(t，J＝ 2.0Hz，1H)，4.29-4.26(m，1H)，3.50-3.47(m，1H)，2.36(d，J＝14.5Hz，1H)，2.13(d，J＝14.5Hz， 1H)，1.46(s，3H)，1.36(s，3H)；13C NMR(125MHz，CDCl3)δ：174.4，141.3，135.1，130.4，128.9， 127.9，127.0，125.4，124.8，121.2，118.3，112.2，54.8，48.6，46.1，31.4，30.4，27.2；HRMS m/z(ESI) calcd for C22H23N2O([M+H]+)331.1805，found 331.1807。
example 19
Adding a 1, 6-eneyne compound (39.8mg, 0.2mmol) shown in formula 1a, an azoalkylnitrile (76.8mg, 0.4mmol) shown in formula 2b and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-10 (65% yield, d.r. > 20: 1);1H NMR(500MHz，CDCl3)δ：7.70-7.68(m，2H)，7.41-7.38(m，2H)，7.18(t，J＝7.0Hz，1H)，5.40 (t，J＝2.0Hz，1H)，5.31(t，J＝2.5Hz，1H)，4.68-4.65(m，1H)，4.54-4.51(m，1H)，2.29(d，J＝14.5 Hz，1H)，1.87(d，J＝15.0Hz，1H)，1.71-1.67(m，1H)，1.50-1.46(m，1H)，1.37(s，3H)，1.35(s， 3H)，1.00(t，J＝7.5Hz，3H)；13C NMR(125MHz，CDCl3)δ：175.9，143.5，138.8，129.0，125.0， 123.4，120.4，110.6，52.3，48.6，46.4，35.4，33.0，31.9，26.7，9.1；HRMS m/z(ESI)calcd for C18H23N2O([M+H]+)283.1805，found283.1806。
example 20
Adding a 1, 6-eneyne compound (39.8mg, 0.2mmol) shown in formula 1a, an azo compound (92.0mg, 0.4mmol) shown in formula 2c and ethyl acetate (2mL) into a Schlenk bottle, then stirring the reactor under the conditions of air atmosphere and 60 ℃ for reaction, monitoring the reaction progress through TLC until the raw materials disappear (the reaction time is 16 hours), after the reaction is completed, decompressing and concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the residue (the elution solvent is ethyl acetate/n-hexane) to obtain a target product I-11 (78% yield);1H NMR (500MHz，CDCl3)δ：7.62(d，J＝8.5Hz，2H)，7.31(t，J＝8.0Hz，2H)，7.08(t，J＝7.5Hz，1H)， 5.15(t，J＝2.0Hz，1H)，4.97(t，J＝2.5Hz，1H)，4.44-4.41(m，1H)，4.34-4.31(m，1H)，3.46(s， 3H)，2.12(d，J＝2.5Hz，2H)，1.25(s，3H)，1.11(s，3H)，1.00(s，3H)；13C NMR(125MHz，CDCl3)δ：178.1，176.9，144.2，139.0，128.9，124.7，120.0，109.4，51.8，51.4，48.9，48.5，41.6，29.3，29.2， 23.4；HRMS m/z(ESI)calcd for C18H24NO3([M+H]+)302.1751，found 302.1753。
example 21 reaction mechanism control experiment
To the reaction of example 2, 2.4 equivalents of tetramethylpiperidine nitroxide (TEMPO) or 2, 6-di-tert-butyl-4-methylphenol (BHT) were added as a radical scavenger, and the yield of the target product of the reaction was almost 0%, indicating that the reaction did proceed through the radical reaction.
It follows that the possible reaction mechanism of the present invention can be deduced as shown in the following formula:
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (8)
1. A method for cyanoalkylation/cyclization reaction of 1, 6-enyne compounds and azoalkylnitriles, comprising the steps of:
adding a 1, 6-eneyne compound shown in formula 1, an azoalkyl nitrile shown in formula 2 and a solvent into a Schlenk reaction bottle, placing the reaction bottle at a certain temperature under the air atmosphere condition, stirring for reaction, monitoring the reaction process by TLC or GC until the raw materials are completely reacted, and performing post-treatment to obtain a cyclized product 2-pyrrolidone compound (I);
in the compounds represented by formula 1, formula 2 and formula I, R1Selected from hydrogen, C5-C14Aryl radical, C1-C10Alkyl radical, C1-C6An acyl group;
R2selected from hydrogen, C1-C6Alkyl radical, C5-C14An aryl group;
R3is selected from C1-C8Alkyl radical, C5-C14An aryl group;
R4is selected from C1-C6Alkyl radical, C5-C14An aryl group;
R5is selected from C1-C6Alkyl radical, C5-C14An aryl group;
wherein each R is1-R5The aryl, alkyl and acyl groups having the number of carbon atoms in the substituents are optionally substituted by a substituent selected from the group consisting of halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
EWG ═ CN or COOMe.
2. The method of claim 1, wherein R is1Is selected from C1-C10Alkyl radical, C5-C14An aryl group; wherein said C1-C10Alkyl radical, C5-C14Aryl is optionally substituted by a substituent selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
R2selected from hydrogen;
R3is selected from C1-C8Alkyl radical, C5-C14Aryl, wherein said C1-C6Alkyl radical, C5-C14Aryl is optionally substituted by a substituent selected from halogen, C1-C6Alkyl radical, C1-C6Alkoxy radical, C5-C14Aryl, halogen substituted C1-C6Alkyl, -NO2、-CN、C1-C6alkyl-C (═ O) -, C1-C6alkyl-OC (O ═ O) -;
R4is selected from C1-C6An alkyl group;
R5is selected from C1-C6An alkyl group.
3. The method according to any one of claims 1-2, wherein the solvent is selected from one or more of ethyl acetate, acetonitrile, toluene, N-dimethylformamide, and water.
4. The process according to claim 3, wherein the solvent is acetonitrile.
5. A method according to any one of claims 1 to 4, wherein the defined temperature is 40 to 80 ℃, preferably 60 ℃.
6. The process according to any one of claims 1 to 5, wherein the time required for complete reaction of the starting materials is from 12 to 20 hours, preferably 16 hours.
7. The process according to any one of claims 1 to 6, wherein the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 1.2 to 1: 3, preferably the molar ratio of the 1, 6-enyne compound of formula 1 to the azoalkylnitrile of formula 2 is 1: 2.
8. The method according to any of claims 1-7, characterized in that the post-processing operation is as follows: extracting the reaction solution after the reaction is finished with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove a solvent, and separating the residue by column chromatography, wherein the elution solvent is: ethyl acetate/n-hexane to obtain the target product 2-pyrrolidone compound (I).
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